Guanidine Derivatives of Quinazoline-2,4(1H,3H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents.

Quinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1H,3H)-diones and quinazoline-4(3H)-one guanidine derivatives. In the present work, novel N1,N3-bis-substituted quinazoline-2,4(1H,3H)-dione derivatives bearing two guanidine moieties were synthesized and pharmacologically profiled. The most potent NHE-1 inhibitor 3a also possesses antiplatelet and intraocular-pressure-reducing activity. Compound 4a inhibits NO synthesis and IL-6 secretion in murine macrophages without immunotoxicity and alleviates neutrophil infiltration, edema, and tissue lesions in a model of LPS-induced acute lung injury. Hence, we considered quinazoline derivative 4a as a potential agent for suppression of cytokine-mediated inflammatory response and acute lung injury.

Synthesis of 2-chloropurine ribosides with chiral amino acid amides at C6 and their evaluation as A1 adenosine receptor agonists.

A series of purine ribonucleosides bearing chiral amino acid amides at the C6 position of 2-chloropurine was synthesized. Molecular docking of the synthesized analogs of 2-chloroadenosine by their affinity for A1 adenosine receptors (A1ARs) was conducted. The investigation of A1AR stimulating activity of synthesized nucleosides was carried out in a model of an isolated mouse atrium. We have shown that derivatives with tyrosine, valine, and serine residues exhibit the properties of A1AR partial agonists. Animal experiments in the open field test have shown that these compounds have different profiles of psychoactive action. These nucleosides have an ophthalmic hypotensive effect and reduce intraocular pressure in a manner slightly inferior to that of timolol and brimonidine. The synthesized nucleosides can be the basis for further design and synthesis of new A1AR agonists.

Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors.

The Na+/H+ exchanger isoform 1 (NHE-1) attracts ongoing attention as a validated drug target for the management of cardiovascular and ocular diseases owing to cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. Herein we report novel NHE-1 inhibitors realized via functionalization of N1-alkyl quinazoline-2,4(1H,3H)-dione and quinazoline-4(3H)-one with N-acylguanidine or 3-acyl(5-amino-1,2,4-triazole) side chain. Lead compounds show activity in a nanomolar range. Their pharmacophoric features were elucidated with neural network modeling. Several compounds combine NHE-1 inhibition with antiplatelet activity. Compound 6b reduces intraocular pressure in rats and effectively inhibits the formation of glycated proteins. Compounds 3e and 3i inhibit pro-inflammatory activation of murine macrophages, LPS-induced interleukin-6 secretion and also exhibit antidepressant activity similar to amiloride. Hence, novel compounds represent an interesting starting point for the development of agents against cardiovascular diseases, thrombotic events, excessive inflammation, long-term diabetic complications and glaucoma.